A Compendium of AR Splice Variants in Metastatic Castration-Resistant Prostate Cancer.

Treatment-induced AR alterations, including AR alternative splice variants (AR-Vs), have been extensively linked to harboring roles in primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer and therefore have gained momentum. Our aim was to uniformly determine recurrent AR-Vs in metastatic castration-resistant prostate cancer (mCRPC) using whole transcriptome sequencing in order to assess which AR-Vs might hold potential diagnostic or prognostic relevance in future research. This study reports that in addition to the promising AR-V7 as a biomarker, AR45 and AR-V3 were also seen as recurrent AR-Vs and that the presence of any AR-V could be associated with higher AR expression. With future research, these AR-Vs may therefore harbor similar or complementary roles to AR-V7 as predictive and prognostic biomarkers in mCRPC or as proxies for abundant AR expression.

A Critical Review of the Biochemical Mechanisms and Epigenetic Modifications in HIV- and Antiretroviral-Induced Metabolic Syndrome.

Metabolic syndrome (MetS) is a non-communicable disease characterised by a cluster of metabolic irregularities. Alarmingly, the prevalence of MetS in people living with Human Immunodeficiency Virus (HIV) and antiretroviral (ARV) usage is increasing rapidly. This study aimed to look at biochemical mechanisms and epigenetic modifications associated with HIV, ARVs, and MetS. More specifically, emphasis was placed on mitochondrial dysfunction, insulin resistance, inflammation, lipodystrophy, and dyslipidaemia. We found that mitochondrial dysfunction was the most common mechanism that induced metabolic complications. Our findings suggest that protease inhibitors (PIs) are more commonly implicated in MetS-related effects than other classes of ARVs. Furthermore, we highlight epigenetic studies linking HIV and ARV usage to MetS and stress the need for more studies, as the current literature remains limited despite the advancement in and popularity of epigenetics.

Assessment of Utilization of Post Exposure Prophylaxis (PEP) among HIV-Exposed Individuals in a Tertiary Hospital, Northwest Nigeria.

BACKGROUND: Human Immunodeficiency Virus (HIV) post-exposure prophylaxis (PEP) has been documented to be effective in preventing HIV in exposed individuals. World Health Organization (WHO) recommends that every individual exposed should be treated within 72hours. We aimed to assess the utilization of PEP among clients in a tertiary facility in Northwest, Nigeria. METHODS: A retrospective study was conducted in Barau Dikko Teaching Hospital (BDTH), a tertiary hospital in Kaduna, Nigeria involving all clients who assessed HIV PEP between January 2016 - December 2019. Data collection sheet was used to document the sociodemographic parameters of clients, sources/circumstances of infection, client HIV status, source HIV status and the interval between exposure and commencement of PEP. Analysis of data was done using IBM SPSS version 23. RESULTS: Analysis of 136 complete records was done, mean age was 31.97± 10.24 years, 77 (56.6%) were females, 102 (75%) were due to occupational exposures involving mostly nurses and medical and nursing students while 26 (76.5%) of non-occupational exposures were attributed to rape. The PEP service was assessed by 119 (87.5%) under 72hours but 120 (88.2%) never returned for follow-up. Source of exposure and HIV status of source were significantly associated with the time of assessing PEP. Statistical significance is determined by a p value of < 0.05. CONCLUSION: A major proportion of those that assessed PEP did so in less than 72 hours which is the recommended time by WHO but follow-up and rescreening was poor. There is need for active follow-up of clients that assess the service and increased public health enlightenment on availability and effect of PEP when assessed at the appropriate time.

CONTEXTE: La prophylaxie post-exposition (PPE) du virus de l'immunodéficience humaine (VIH) s'est avérée efficace pour prévenir le VIH chez les personnes exposées. L'Organisation mondiale de la santé (OMS) recommande que chaque individu exposé soit traité dans les 72 heures. Nous avons cherché à évaluer l'utilisation de la PEP dans un établissement tertiaire du Nord-Ouest du Nigeria en examinant les caractéristiques sociodémographiques, le type d'exposition, le moment de l'évaluation des soins et du suivi. MÉTHODES: Il s'agit d'une étude rétrospective menée au Barau Dikko Teaching Hospital (BDTH), un hôpital tertiaire à Kaduna, au Nigeria, impliquant tous les clients qui ont évalué la PEP du VIH entre janvier 2016 et décembre 2019. La feuille de collecte de données a été utilisée pour recueillir les paramètres sociodémographiques des clients, les sources/circonstances de l'infection, le statut VIH du client et de la source et l'intervalle entre l'exposition et le début de la PEP. L'analyse des données a été réalisée à l'aide d'IBM SPSS version 23. RÉSULTATS: 136 dossiers complets ont été analysés. L'âge moyen était de 31,97± 10,24 ans, 77 (56,6%) étaient des femmes. 102 (75%) étaient dus à des expositions professionnelles impliquant principalement des infirmières et des étudiants en médecine et en soins infirmiers, tandis que 26 (76,5%) des expositions non professionnelles étaient attribuées à des viols. 119 (87,5%) ont évalué la PEP sous 72 heures mais 120 (88,2%) ne sont jamais revenus pour un suivi. La source d'exposition et le statut VIH de la source étaient significativement associés au délai d'évaluation de la PEP (p ≤0,05). CONCLUSION: Un nombre significatif de ceux qui ont évalué la PEP étaient des professionnels plus jeunes dans le délai recommandé par l'OMS, mais le suivi et le redépistage étaient faibles. Il faut un suivi actif des clients qui évaluent le service et une éducation accrue sur la disponibilité et l'effet de la PPE lorsqu'elle est évaluée au moment opportun. MOTS CLÉS: Virus de l'immunodéficience humaine (VIH), prophylaxie post-exposition (PPE), médicaments antirétroviraux (ARV), expositions professionnelles et non professionnelles.

Level of adherence and associated factors among HIV-positive adolescents on antiretroviral therapy in Cameroon.

Aim: Globally, there were over 250 000 new HIV infections among adolescents in 2017, with a higher proportion of these in sub-Saharan Africa. In Cameroon, UNICEF estimated over 4 200 new HIV infections in adolescents in 2015; by 2016, there were over 40 000 adolescents who had HIV. Given that the number of adolescents living with HIV in Cameroon is on the increase, there is a need to better understand the factors influencing adherence to treatment. The objective of this study was to assess the factors associated with adherence among adolescents in Cameroon. Methods: A cross-sectional study was conducted. A total of 460 HIV+ adolescents who were receiving antiretroviral therapy were sampled randomly from nine health facilities. Questionnaires and data extraction forms were used to collect data. Descriptive (frequencies and proportions) and inferential (chi-square and multivariate logistic regression) statistical analyses methods were used to analyse the data. Statistical significance was set at p = 0.05 and 95% confidence level. Results: The level of adherence to antiretroviral therapy among the adolescents was 83%. Twelve out of 30 independent variables examined showed significant statistical association with adherence at the bivariate level. In the multivariable logistic regression analyses, however, only two variables significantly predicted adherence - experiencing side effects (AOR = 2.63; 95% CI = 1.14, 6.09; p = 0.02), and internalized stigma (AOR = 2.51; 95% CI = 1.04, 6.04; p = 0.04). Conclusion: Adherence to treatment among adolescents in Cameroon was found to be suboptimal. There is a need for more individualized, targeted medication counselling for adolescents and their guardians as well as strategies to reduce internalized stigma and improve adherence to antiretroviral treatment.

Demand and Supply Motivations for Antiretroviral Drugs in Illicit Street Markets: The Case of Atlanta, Georgia.

We studied the motivations behind supply and demand of antiretroviral drugs (ARVs) in the illicit street markets of the metropolitan statistical area of Atlanta, Sandy Springs, and Roswell, Georgia. We found that these two market actions were largely interdependent: 39.53% of participants said that they sold their ARVs to pay for personal needs, and 20.93% said that they bought ARVs because they had previously sold them to pay for personal needs. The pattern that emerged suggests that illicit street markets have become mechanisms through which HIV patients cooperate to achieve competing goals: cover personal needs and keep up, however imperfectly, with their medication regime. We also found that HIV patients used illicit street markets because they faced institutional deficiencies, such as exclusion from the Ryan White/ADAP program, long waiting times to see a doctor, and prescription delays.

Inhibition of androgen receptor transactivation function by adenovirus type 12 E1A undermines prostate cancer cell survival.

BACKGROUND: Mutations or truncation of the ligand-binding domain (LBD) of androgen receptor (AR) underlie treatment resistance for prostate cancer (PCa). Thus, targeting the AR N-terminal domain (NTD) could overcome such resistance. METHODS: Luciferase reporter assays after transient transfection of various DNA constructs were used to assess effects of E1A proteins on AR-mediated transcription. Immunofluorescence microscopy and subcellular fractionation were applied to assess intracellular protein localization. Immunoprecipitation and mammalian two-hybrid assays were used to detect protein-protein interactions. qRT-PCR was employed to determine RNA levels. Western blotting was used to detect protein expression in cells. Effects of adenoviruses on prostate cancer cell survival were evaluated with CellTiter-Glo assays. RESULTS: Adenovirus 12 E1A (E1A12) binds specifically to the AR. Interestingly, the full-length E1A12 (266 aa) preferentially binds to full-length AR, while the small E1A12 variant (235 aa) interacts more strongly with AR-V7. E1A12 promotes AR nuclear translocation, likely through mediating intramolecular AR NTD-LBD interactions. In the nucleus, AR and E1A12 co-expression in AR-null PCa cells results in E1A12 redistribution from nuclear foci containing CBX4 (also known as Pc2), suggesting a preferential AR-E1A12 interaction over other E1A12 interactors. E1A12 represses AR-mediated transcription in reporter gene assays and endogenous AR target genes such as ATAD2 and MYC in AR-expressing PCa cells. AR-expressing PCa cells are more sensitive to death induced by a recombinant adenovirus expressing E1A12 (Ad-E1A12) than AR-deficient PCa cells, which could be attributed to the increased viral replication promoted by androgen stimulation. Targeting the AR by E1A12 promotes apoptosis in PCa cells that express the full-length AR or C-terminally truncated AR variants. Importantly, inhibition of mTOR signaling that blocks the expression of anti-apoptotic proteins markedly augments Ad-E1A12-induced apoptosis of AR-expressing cells. Mechanistically, Ad-E1A12 infection triggers apoptotic response while activating the PI3K-AKT-mTOR signaling axis; thus, mTOR inhibition enhances apoptosis in AR-expressing PCa cells infected by Ad-E1A12. CONCLUSION: Ad12 E1A inhibits AR-mediated transcription and suppresses PCa cell survival, suggesting that targeting the AR by E1A12 might have therapeutic potential for treating advanced PCa with heightened AR signaling.

Antiretroviral therapy supply chain quality control and assurance in improving people living with HIV therapeutic outcomes in Cameroon.

BACKGROUND: Evaluation of medication efficacy and safety is an essential guarantee to successful therapeutic outcome in public health practices. However, larger distribution chain supply in developing countries such as Cameroon is often challenged by counterfeit drugs, poor manufacturing, storage and degradation leading to health and patient adverse consequences. Yet, access to supply chain management in strengthening ARVs quality assurance and outcomes remains poorly documented. More than 53,000 patients have been enrolled on free ARVs medications, but little is documented on quality assurance and validity of safety for affected populations along the supply chain management since 2008. METHODS: The cross sectional study was conducted in ARVs distribution units and centers in central, littoral and south west regions of Cameroon. ARVs drugs samples included Nevirapine, Efavirenz, and fixed dose combinations of Zidovudine + Lamivudine, Lamivudine + Stavudine and Zidovudine + Lamivudine + Nevirapine. Drugs packaging and labeling was assessed and galenic assays were performed at National Laboratory of quality Control of Medications and Expertise (LANACOME), Yaoundé, Cameroon. RESULTS: The study covered 16 structures located in eight different towns including the central ARVs store, two regional pharmaceutical procurement centers and thirteen HIV approved treatment centers and management units. A total of 35 ARVs products were collected. Only eight ARVs drugs containing Lamivudine and Stavudine presented with white stains on tablets, however these drugs were standard for all other tests performed. The others 28 ARVs products were standards to all assays performed. CONCLUSION: We concluded that ARVs drugs freely accessible and distributed to PLWHA are of good quality in Cameroon. However, with the increase number of patients under HAART since 2013, adoption of "Test and Treat" approach to reach the 90-90-90 goals and with the implementation of new national antiretroviral regimen guidelines and molecules such as boosted protease inhibitors, continuous quality control and assurance surveillance, monitoring and evaluation is recommended. Assessment of quality of formulations that are more susceptible to degradation such as pediatric formulations for averting the rising multidrug resistance trend is also desired.

Challenges and opportunities of optimal breastfeeding in the context of HIV option B+ guidelines.

BACKGROUND: In 2013, the World Health Organization released a new set of guidelines widely known as Option B+. Prior to that there were guidelines released in 2010. Option B+ recommends lifelong antiretroviral treatment for all pregnant and breastfeeding women living with Human Immunodeficiency Virus. The study aimed at investigating challenges and opportunities in implementing Infant and Young Child Feeding in the context of Prevention of Mother To Child Transmission (PMTCT) guidelines among HIV positive mothers of children aged 0-24 months. The study also examined implications presented by implementing the 2013 PMTCT consolidated guidelines in the transition phase from the 2010 approach in Zambia. METHODS: A mixed methods approach was employed in the descriptive cross sectional study utilizing semi structured questionnaires and Focused Group Discussions. Further, data was captured from the Health Information Management System. RESULTS: During the PMTCT transition, associated needs and challenges in institutionalizing the enhanced guidelines from option A and B to option B+ were observed. Nonetheless, there was a decline in Mother to Child Transmission (MTCT) of HIV rates with an average of 4%. Mothers faced challenges in complying with optimal breastfeeding practices owing to lack of community support systems and breast infections due to poor breast feeding occasioned by infants' oral health challenges. Moreover, some mothers were hesitant of lifelong ARVs. Health workers faced programmatic and operational challenges such as compromised counseling services. CONCLUSION: Despite the ambitious timelines for PMTCT transition, the need to inculcate new knowledge and vary known practice among mothers and the shift in counseling content for health workers, the consolidated guidelines for PMTCT proved effective. Some mothers were hesitant of lifelong ARVs, rationalizing the debated paradigm that prolonged chemotherapy/polypharmacy may be a future challenge in the success of ART in PMTCT. Conflicting breast feeding practices was a common observation across mothers thus underpinning the need to strongly invigorate Infant and Young Child Feeding information sharing across the continuum of heath care from facility level to community and up to the family; for cultural norms, practices and attitudes enshrined within communities play a vital role in child care.

Assessing Adherence to Antiretroviral Therapy in a Rural Paediatric Cohort in KwaZulu-Natal, South Africa.

Achieving optimal adherence to ARV's in a rural paediatric population is challenging. Monitoring adherence by frequent viral load assay is not always feasible or sustainable in rural communities. A relatively cheaper, reliable, valid and sustainable measure of adherence for children is required for routine management. This study retrospectively assessed adherence outcomes using monthly pill count and viral load data, including reasons reported for non-adherence, in a paediatric cohort in rural KwaZulu-Natal, South Africa. Between 2008 and 2013, 78 children, mean age of 7.1 years, were enrolled in the CAPRISA 052 AIDS Treatment Programme. Monthly treatment adherence by pill count was categorized as either high (≥95 %) or low (<95 %). Overall median monthly adherence to treatment by pill count was 87.8 % at month 6, 88.9 % at month 12 and 90.8 % at month 24. However, the proportion of children with an undetectable viral load (<400 copies/ml) was 84.0 % (63/74), 86.6 % (58/67), and 84.5 % (49/58) at the three time points respectively. Agreement between pill count and viral load showed that only 33.9, 36. 3 and 30.6 % of children were truly adherent by pill count at months 6, 12 and 24 respectively. In conclusion, this treatment programme demonstrated that adherence of >95 % by pill count is not an ideal indicator of virological suppression in children aged 6 months to 13 years. Viral load assessment remains the gold standard for assessing treatment success in this age group.

Differences in antiretroviral safety and efficacy by sex in a multinational randomized clinical trial.

BACKGROUND AND OBJECTIVE: Worldwide, 50% of human immunodeficiency virus (HIV)-infected people are women. This study was to evaluate whether the safety and efficacy outcomes of three initial antiretroviral regimens (ARVs) differed by sex. METHODS: Antiretroviral regimen naive participants from nine countries in four continents were assigned to ARVs with efavirenz (EFV) plus lamivudine-zidovudine, atazanavir (ATV) plus didanosine (ddI)-EC/emtricitabine (FTC) or EFV plus FTC-tenofovir-DF. The primary objective was to estimate the sex difference on efficacy outcome of treatment failure defined as one of the following: 1. Time to 1st of confirmed virologic failure, 2. WHO Stage 4 progression or 3. death with hazard ratio (HR) and 95% confidence interval (CI) from adjusted Cox regression models. RESULTS: In all, 739 (47%) women and 832 (53%) men with HIV were evaluated. Women had higher pretreatment CD4+(182 vs 165 cells/mm(3); P < 0.001) and lower HIV-1 RNA (4.9 log10 vs 5.2 log10 copies/ml; P < 0.001) compared to men. Association of sex with time to regimen failure differed by treatment arm (P = 0.018). For atazanavir plus didanosine-EC plus emtricitabine, women had a longer time to treatment failure compared to men [adjusted HR (aHR) = 0.59; 95% CI 0.40-0.87]. Women were less likely to prematurely discontinue treatment prematurely (aHR = 0.74; 95% CI 0.56-0.98). Women assigned to efavirenz plus lamivudine-zidovudine were more likely to have a primary safety event compared to men (aHR = 1.49; 95% CI 1.18-1.88). CONCLUSION: Antiretroviral efficacy and safety differed by sex in this study. Consideration of potential effects of sex on antiretroviral outcomes is important for the design of future clinical trials and for HIV treatment guidelines.

Pharmacokinetics of Antiretroviral Agents in Pregnant Individuals Living With HIV: Current Status and Considerations for Study Design and Interpretation.

Determining the appropriate dosing regimens of antiretroviral (ARV) drugs for pregnant individuals living with HIV-1 infection is critical to maximize maternal health and prevent perinatal HIV transmission. Throughout pregnancy, pharmacokinetics (PK) of ARVs can be significantly altered due to physiological, anatomic, and metabolic changes. As such, conducting PK studies of ARVs during pregnancy is crucial to optimize dosing regimens. In this article, we summarize available data, key issues, challenges, and considerations in interpreting results of ARV PK studies in pregnant individuals. Discussion topics include the choice of the reference population (postpartum vs historical control), pregnancy trimester-dependent changes in ARV PK, effects of pregnancy on once- versus twice-daily dosing, factors to consider for ARVs that are administered with a PK booster such as ritonavir and cobicistat, and considerations when evaluating the effects of pregnancy on unbound ARV concentrations. Common approaches for the translation of the results into clinical recommendations and rationales and considerations when making clinical recommendations are summarized. Currently, limited PK data in pregnancy are available with long-acting ARVs. Collection of PK data to characterize the PK profile of long-acting ARVs is an important goal shared by many stakeholders.

Development of a multivalent adjuvanted inactivated vaccine against variant arthrotropic avian reoviruses.

Variant avian reoviruses (ARVs) are economically important emerging pathogens of poultry, which mainly affect young broiler chickens and cause significant production losses. Currently, there are no effective commercial vaccines available for control and prevention of emerging variant ARVs. In this study, monovalent inactivated adjuvated (20% Emulsigen D) broiler breeder vaccines containing antigens from ARV genotype cluster (C) group -2, -4, -5, or -6, and a multivalent vaccine containing antigens from all the four indicated genotypic cluster groups were developed and evaluated for their efficacy in protecting broiler progenies against homologous or heterologous ARV challenge. The use of monovalent or multivalent inactivated vaccines in a prime-boost immunization strategy induced the production of ARV specific antibodies in broiler breeders. The maternal antibodies were effectively transferred to broiler progenies. Broiler progenies obtained from immunized breeders demonstrated milder clinical symptoms and reduced gross and histopathological lesions after homologous ARV challenge. More severe gross and histological lesions were observed in challenged progenies from unvaccinated broiler breeders. However, cross protection was not observed when either of the monovalent-vaccine groups were challenged with a heterologous virus. In addition, the progenies from the unvaccinated ARV challenged control or heterologous ARV challenged vaccinated groups had significantly reduced body weight gain (p < 0.01) than the unchallenged-control, challenged-multivalent, or homologous ARV-challenged monovalent vaccine groups. However, homologous ARV challenged progenies in the multivalent or monovalent vaccine groups had similar body weight gain as the control unchallenged group with significantly reduced viral load (p < 0.01) in the gastrocnemius tendon tissue. This study indicates that broad-spectrum protection of broiler progenies from variant ARV infections is feasible through the development of multivalent vaccines after proper characterization, selection and incorporation of multiple antigens based on circulating ARV genotypes in targeted regions.

Antiretrovirals Promote Metabolic Syndrome through Mitochondrial Stress and Dysfunction: An In Vitro Study.

The prevalence of metabolic syndrome MetS in HIV-infected patients on chronic antiretroviral (ARV) therapy continues to rise rapidly, with an estimated 21% experiencing insulin resistance. The progression of insulin resistance is strongly related to mitochondrial stress and dysfunction. This study aimed to draw links between the singular and combinational use of Tenofovir disoproxil fumarate (TDF), Lamivudine (3TC), and Dolutegravir (DTG) on mitochondrial stress and dysfunction as an underlying mechanism for insulin resistance following a 120 h treatment period using an in vitro system of human liver cells (HepG2). The relative protein expressions of pNrf2, SOD2, CAT, PINK1, p62, SIRT3, and UCP2, were determined using Western blot. Transcript levels of PINK1 and p62 were assessed using quantitative PCR (qPCR). ATP concentrations were quantified using luminometry, and oxidative damage (malondialdehyde (MDA) concentration) was measured using spectrophotometry. The findings suggest that despite the activation of antioxidant responses (pNrf2, SOD2, CAT) and mitochondrial maintenance systems (PINK1 and p62) in selected singular and combinational treatments with ARVs, oxidative damage and reduced ATP production persisted. This was attributed to a significant suppression in mitochondrial stress responses SIRT3 and UCP2 for all treatments. Notable results were observed for combinational treatments with significant increases in pNrf2 (p = 0.0090), SOD2 (p = 0.0005), CAT (p = 0.0002), PINK1 (p = 0.0064), and p62 (p = 0.0228); followed by significant decreases in SIRT3 (p = 0.0003) and UCP2 (p = 0.0119) protein expression. Overall there were elevated levels of MDA (p = 0.0066) and decreased ATP production (p = 0.0017). In conclusion, ARVs induce mitochondrial stress and dysfunction, which may be closely associated with the progression of insulin resistance.

HIV Latency and Nanomedicine Strategies for Anti-HIV Treatment and Eradication.

Antiretrovirals (ARVs) reduce Human Immunodeficiency Virus (HIV) loads to undetectable levels in infected patients. However, HIV can persist throughout the body in cellular reservoirs partly due to the inability of some ARVs to cross anatomical barriers and the capacity of HIV-1 to establish latent infection in resting CD4+ T cells and monocytes/macrophages. A cure for HIV is not likely unless latency is addressed and delivery of ARVs to cellular reservoir sites is improved. Nanomedicine has been used in ARV formulations to improve delivery and efficacy. More specifically, researchers are exploring the benefit of using nanoparticles to improve ARVs and nanomedicine in HIV eradication strategies such as shock and kill, block and lock, and others. This review will focus on mechanisms of HIV-1 latency and nanomedicine-based approaches to treat HIV.

Antiretroviral drugs efavirenz, dolutegravir and bictegravir dysregulate blood-brain barrier integrity and function.

The implementation of combined antiretroviral therapy (cART) significantly reduces the mortality associated with human immunodeficiency virus (HIV) infection. However, complications such as HIV-associated neurocognitive disorders (HAND) remain a major health concern. We hypothesized that the toxicity of antiretroviral drugs (ARVs) may contribute to the pathogenesis of HAND in addition to cerebral viral infection. To address this question, we evaluated the impact of HIV integrase strand transfer inhibitors (dolutegravir and bictegravir), and a non-nucleoside reverse transcriptase inhibitor (efavirenz) on the integrity and permeability of various human and mouse blood-brain barrier (BBB) models, in vitro, ex vivo and in vivo. We observed a significant downregulation of tight junction proteins (TJP1/Tjp1, OCLN/Ocln and CLDN5/Cldn5), upregulation of proinflammatory cytokines (IL6/Il6, IL8/Il8, IL1ß/Il1ß) and NOS2/Nos2, and alteration of membrane-associated transporters (ABCB1/Abcb1a, ABCG2/Abcg2 and SLC2A1/Slc2a1) mRNA expression, in vitro, in human (hCMEC/D3) and primary cultures of mouse microvascular endothelial cells, and ex vivo in isolated mouse brain capillaries treated with efavirenz, dolutegravir, and/or bictegravir. We also observed a significant increase in BBB permeability in vivo following treatment with the selected ARVs in mice applying NaF permeability assay. Taken together, these results suggest that clinically recommended integrase strand transfer inhibitors such as dolutegravir may exacerbate HIV-associated cerebrovascular pathology, which may contribute to the associated short-term neuropsychiatric side effects and the high incidence of mild forms of HAND reported in the clinical setting.

The Impact of Certain Pharmacogenetic Differences on the Metabolism of Antiretroviral Drugs Used in A Black South African Population.

BACKGROUND: Genetic polymorphism of drug-metabolising enzymes and transporters may influence the effect and toxicity of antiretroviral drugs. OBJECTIVES: To determine and compare the minimum allele frequency of 20 single nucleotide polymorphisms (SNPs) with possible involvement in the metabolism of the antiretroviral drugs with other populations. To investigate the influence of these variants on Reverse transcriptase, Protease and Integrase strand transfer inhibitor drugs. METHOD: DNA samples were collected from 1489 subjects. All SNPs with a gene call score of > 0.6 were selected for genotyping. The R package calculated call rates, MAF and Hardy-Weinberg equilibrium (HWE), test p-values, and Chi-squared analysis were performed on the data. The Fisher's exact test compared the allele frequencies between the populations. RESULTS: The highest similarities in minimum allele frequency (MAF) were between the Prospective Urban and Rural Epidemiological group (PURE), a Black population in South Africa, and the Yoruba and Luhya populations in Africa. The following SNPs were identified with a possible effect on metabolism: CYP2B6 rs28399494 (MAF 11%) is indicated in the toxicity of Efavirenz and Nevirapine. CYP3A5 rs776746 (MAF 17%) and CYP3A4 rs2749674 (MAF 23%) both cause an increase in the metabolism of the protease inhibitors. The very low MAF values for both SCL01B1 rs4149056 (MAF 0.6%) and ABCC rs717620 (MAF 2.8%) are indications that OATP1B1 transport function and glomerular filtration tempo will not be compromised. The high MAF value of 30% for UGTA1 rs10929302 can result in hyperbilirubinemia, which can decrease the clearance of Dolutegravir. CONCLUSION: These results show a possibility of kidney protection and an increase in bilirubin in this population.

HIV-antiretrovirals in river water from Gauteng, South Africa: Mixed messages of wastewater inflows as source.

South Africa has the highest number of people living with the human immunodeficiency virus (HIV). High usage of HIV-antiretroviral drugs (ARVs) for the treatment of the acquired immunodeficiency syndrome (AIDS) leads to the presence of ARVs in the environment. Wastewater is a major contributor of pharmaceuticals in surface and drinking water as wastewater treatment plants (WWTPs) are not designed to remove these compounds. Pharmaceuticals in the environment pose risks and the effects of ARVs on non-target organisms are largely unknown. The concentrations of ARVs in surface water upstream and downstream from WWTPs in rivers were determined. The samples were extracted by solid-phase extraction and analysed by using liquid chromatography coupled with a quadrupole time-of-flight mass spectrometer. Five ARVs were quantified, mostly in downstream samples of the WWTPs, indicating wastewater as a source of ARVs, but this was not apparent in all cases. Nevirapine, lopinavir, and efavirenz were frequently detected; the highest concentrations being lopinavir and efavirenz at 38 µg/L and 24 µg/L, respectively. Aquatic ecosystems are at risk due to the constant input of pharmaceuticals that include large amounts of everyday use and the release of ARVs. This study highlights the potential of increased water pollution worldwide should more people consume increased quantities of pharmaceuticals.

"Whatever is in the ARVs, is Also in the PrEP" Challenges Associated With Oral Pre-exposure Prophylaxis Use Among Female Sex Workers in South Africa.

Background: The national policy on oral pre-exposure prophylaxis (PrEP) for female sex workers (FSWs) was instituted in South Africa in 2016. FSWs were targeted for PrEP due to a Human immunodeficiency virus (HIV) prevalence of 57.7%, which is higher than the prevalence of 19.07% among the general population. Research from demonstration studies has shown that uptake of PrEP has been slower than anticipated, and the purpose of this study was to explore barriers to the uptake of PrEP among FSWs. Methods: An in-depth qualitative study was conducted with 39 participants, 30 individual participants, and nine focus group participants. Eleven participants consisted of peer educators and two health workers from a sex work and PrEP distribution organization, the rest of the participants (1) were FSWs. Results: The majority of participants mentioned that little distinction was made between PrEP and antiretrovirals (ARVs) taken by FSWs living with HIV. PrEP was not distributed through public health care facilities, and health workers unknowingly labeled PrEP as ARVs. Consequently, health workers seen as experts created suspicion and contributed to the mistrust of PrEP among FSWs due to mixed messages, and equating PrEP to ARVs reduced uptake. Furthermore, failure to make a clear distinction between oral PrEP and ARVs resulted in accusations of lying, denialism, and deception leveled at users of PrEP by FSWs using ARVs, and sometimes by clients and intimate partners. FSWs using PrEP reported feeling stigmatized and thrust into interpersonal conflict with their peers after choosing PrEP, leading to broken relationships, and some resorting to taking PrEP privately or discontinuing PrEP altogether. Conclusion: Pre-exposure prophylaxis as an ARV targeted for the prevention of HIV among high-risk groups was found to be stigmatizing. The distinctive use of PrEP and ARVs should be correctly explained to users to minimize confusion, enable differentiation and reduce interpersonal conflict. Cohesion among sex work organizations and public health care facilities is needed to disseminate the correct knowledge on PrEP. A non-stigmatizing approach to the distribution of PrEP may serve to increase uptake and adherence.

Development of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants.

The role of the androgen receptor (AR) in the progression of prostate cancer (PCa) is well established and competitive inhibition of AR ligand binding domain (LBD) has been the mainstay of antiandrogen therapies for advanced and metastatic disease. However, the efficacy of such drugs is often limited by the emergence of resistance, mediated through point mutations and receptor splice variants lacking the AR-LBD. As a result, the prognosis for patients with malignant, castrate-resistant disease remains poor. The amino terminal domain (NTD) of the AR has been shown to be critical for AR function. Its modular activation function (AF-1) is important for both gene regulation and participation in protein-protein interactions. However, due to the intrinsically disordered structure of the domain, its potential as a candidate for therapeutic intervention has been generally overlooked. In this article, we describe the design and development of a functional cell-based assay aimed at identifying small-molecule inhibitors of the AR-NTD. We demonstrate the suitability of the assay for high-throughput screening platforms and validate two initial hits emerging from a small, targeted, library screen in PCa cells.

The Potential of Spirulina platensis to Ameliorate the Adverse Effects of Highly Active Antiretroviral Therapy (HAART).

The human immunodeficiency virus (HIV) is one of the most prevalent diseases globally. It is estimated that 37.7 million people are infected with HIV globally, and 8.2 million persons are infected with the virus in South Africa. The highly active antiretroviral therapy (HAART) involves combining various types of antiretroviral drugs that are dependent on the infected person's viral load. HAART helps regulate the viral load and prevents its associated symptoms from progressing into acquired immune deficiency syndrome (AIDS). Despite its success in prolonging HIV-infected patients' lifespans, the use of HAART promotes metabolic syndrome (MetS) through an inflammatory pathway, excess production of reactive oxygen species (ROS), and mitochondrial dysfunction. Interestingly, Spirulina platensis (SP), a blue-green microalgae commonly used as a traditional food by Mexican and African people, has been demonstrated to mitigate MetS by regulating oxidative and inflammatory pathways. SP is also a potent antioxidant that has been shown to exhibit immunological, anticancer, anti-inflammatory, anti-aging, antidiabetic, antibacterial, and antiviral properties. This review is aimed at highlighting the biochemical mechanism of SP with a focus on studies linking SP to the inhibition of HIV, inflammation, and oxidative stress. Further, we propose SP as a potential supplement for HIV-infected persons on lifelong HAART.